A pattern of brain damage is often found at autopsy in individuals whose clinical history includes frequent episodes of prolonged epileptic seizures (Corsellis et al 1976; a list of complete citations is provided below). Such epilepsy-related brain damage occurs most frequently in association with a type of epilepsy known as temporal lobe epilepsy (also referred to as psychomotor epilepsy or complex partial seizures). In this type of epilepsy, episodes of seizure activity may be quite prolonged (i.e., they may last for several hours), and they are often very difficult to control with any drugs currently available. The mechanism by which prolonged seizures give rise to brain damage was unknown until recent animal studies provided evidence linking such damage to excitatory transmitter systems in the brain, primarily the glutamate transmitter system (Olney et al 1986).
It is impossible to demonstrate with certainty that any seizure or seizure-related brain damage in a non-human animal falls within the proper definition of "epilepsy." Therefore, seizures and brain damage in lab animals which appear to be comparable to human epilepsy are referred to as "epileptiform" rather than "epilepsy." In lab animals, epileptiform seizures and brain damage can be induced by convulsant drugs, as discussed below. They also occur spontaneously in some strains of lab animals which are specially bred to exhibit epileptiform symptoms. Despite limitations, animal models offer the only methods available to researchers for studying epilepsy, short of tests on humans. Therefore, researchers use animal models to test drugs for anti-convulsant potential, and a great deal of research has been devoted to identifying drugs which generate epileptiform manifestations (i.e., seizure activity) and consequences (particular types of brain damage) that most closely resemble the manifestations and consequences of epilepsy in humans.
Three of the convulsant drugs that are of interest to researchers studying epilepsy are (1) kainic acid, a glutamate agonist (Nadler 1981); (2) pilocarpine, a cholinergic agonist (Clifford et al 1987); and (3) soman, a cholinesterase inhibitor (McLeod et al 1984). In several important respects, both the manifestations and the consequences of severe cases of epilepsy, especially temporal lobe epilepsy, resemble the manifestations and consequences of each of those convulsant drugs. Each of those substances can cause continuous seizure activity which can persist for hours, similar to "status epilepticus" in humans. In addition, each of those substances causes disseminated brain damage which resembles the damage observed during autopsies of humans who suffered from severe epilepsy.
A number of efforts to treat lab animals against convulsions induced by kainic acid, pilocarpine, and soman have focused on tranquilizers and sedatives. Diazepam (sold under the trade name Valium) suppresses seizures induced by these agents, but only at relatively high doses which are overly sedating (Clifford et al 1982; Fuller et al 1981). This makes such agents undesirable, especially as a long-term preventive measure.
Braitman et al 1988 states that a substance referred to as MK-801 (a glutamate antagonist, discussed below) provides some degree of protection against soman, if administered before soman exposure and if used in conjunction with other protective agents. However, recent research by the inventor of the subject application has discovered that when MK-801, phencyclidine, or ketamine were used in an effort to protect lab animals against pilocarpine, the seizure activity was made worse and the outcome was rapidly lethal. Although the reasons for these apparently conflicting results are not entirely clear, both sets of results suggest that interactions between the cholinergic and glutamate receptor systems may be relevant to efforts to provide an effective method for protecting the brain against epileptic seizures and against brain damage which can result from such seizures. The following sections provide information on both the cholinergic and glutamate receptor systems.